1. Field of the Invention
The present invention relates to a medicament for treating arteriosclerosis which comprises pyrimido[2,1-b]-benzothiazole derivative.
Medical treatment for arteriosclerosis aim to prevent the progress of arteriosclerosis and/or to prevent the occurrence thereof. A further object of such a medical treatment is to prevent occurrence of arteriosclerosis when symptoms of the disease have already been recognized.
In order to preclude occurrence of arteriosclerosis, it is necessary to remove the factors which induce the disease, such as hyperlipidemia, smoking or corpulence. On the other hand, it has been pointed out that blood platelets have a close relation to the occurrence of arteriosclerosis, and according to one hypothesis thrombopoiesis is the main cause of arteriosclerosis. Under such circumstances, anticoagulants for inhibiting coagulation of blood platelets have been used as medicaments for prevention of arteriosclerosis.
In one of its aspects, this invention relates to a medicament for alleviating the hyperlipidemia which is considered as the principal factor inducing arteriosclerosis. More particularly, the present invention relates to a medicament containing a pyrimidobenzothiazole derivative as an efficacious ingredient for hyperlipidemia.
According to another aspect, this invention relates to an anticoagulant for inhibiting coagulation of blood platelets, which contains a pyrimidobenzothiazole derivative, as an efficacious ingredient, for controlling blood platelet prostaglandin synthesis thereby to alleviate the symptoms of thrombosed or blocked arteria disease.
2. Description of the Related Art
Heart disease caused by troubles in the coronary arteries are the leading cause of death in the United States of America, and almost all of the patients suffering such diseases are afflicted with arteriosclerosis.
It has been considered such diseases or symptoms have a close relation with improper diet, corpulence, high serum cholesterol level, lack of physical activity, mental stress, hypertension and smoking.
Likewise in Japan, it is anticipated that patients afflicted by such diseases will increase in the future due to similar causes, particularly due to the tendency of modern Japanese to eat high calorie meals similar to the peoples of Europe and America. It may therefore be said that such arteriosclerotic diseases are modern diseases in advanced nations.
Meanwhile, patients who are troubled with hyperlipidemia are seriously affected by increase in lipoproteins, particularly the increase in low density lipoprotein (LDL) or beta-very low density lipoprotein (.beta.-VLDL).
For the symptoms caused by hyperlipidemia, it is known that the precipitation of lipid (esters of long-chain fatty acids and alcohols and analogues thereof) depends upon the lipid content of blood serum and that gruel-like spots are formed by the sedimentation of lipid. Formation and spreading of gruel-like spots can be suppressed or reduced by the use of a drug composition or medicament for eliminating the hyperlipidemia.
The drug compositions which are presently used in clinical applications for eliminating hyperlipidemia have the functions or effects which may be roughly divided into the following groups:
(1) Inhibiting synthesis of cholesterol in liver; PA0 (2) Accelerating catabolism (dissimilation) and discharge of cholesterol; PA0 (3) Suppressing absorption of cholesterol through the intestinal tract; and PA0 (4) Activation of lipase activity of lipoprotein. PA0 (1) Clofibrate[ethyl-2-(p-chlorophenoxy)-2-methylpropionate] and simfibrate; PA0 (2) Thyroxine and Pantetheine; PA0 (3) Cholestyramine and Melinamide; and PA0 (4) Dextran sulfate.
Examples of the drug ingredients which have the functions or effects as classified hereinabove will be set forth below.
However, it has not yet been found that pyrimido[2,1-b]benzothiazole derivatives have the effect of curing hyperlipidemia.
After studies on the pyrimido[2,1-b]-benzothiazole derivatives, we have found that the compounds of this invention have the effect of decreasing LDL and .beta.-VLDL which tend to cause an injury of endothelium and arteriosclerosis. The compounds of this invention have a further effect of inhibiting coagulation of blood platelets, thus preventing blockage of blood flow and suppressing coagulation of blood.
The conventional drugs, which have been called "blood platelet coagulation inhibitors" are used mainly for prevention of formation of thrombus since a once-formed thrombus is hard to re-dissolve or removed from the blood.
On the other hand, it has recently been pointed out that thrombosed diseases, such as ischemic disorder, disorder in cerebral blood vessel and diabetes millitus, are very serious. It is well known that the formation of thrombus is affected by the blood vessel wall, the composition of the blood and the condition of blood flow, and it is further regarded as important to consider the role played by the endothelium of the blood vessels, activation of blood platelets, formation of fibrin, failure of fibrin dissolution system, change in blood flow and reticuloendothelial system. Particularly important factors are adherence of blood platelets on the impaired blood vessel wall, releasing of the contents in blood platelets and coagulation reaction thereof.
Studies on and elucidation of the function of prostaglandin (PG) and derivatives thereof have been pursued. For example, prostaglandin (PG) and derivatives thereof have been synthesized from the components constituting the blood platelet membrane when the blood platelets are stimulated. Specifically, when blood platelets are activated, arachidonic acid is freed from phospholipid of the blood platelet membrane under the action of phospholipase and then acted on by cyclooxygenase to produce PGG.sub.2 and PGH.sub.2 which are PG endoperoxides. Thereafter, these PG endoperoxides react with Thromboxane A.sub.2 synthesis enzyme to product Thromboxane A.sub.3 (TXA.sub.2). The TXA.sub.2 has an extremely high blood platelet coagulation function. On the other hand, the blood vessel wall contains an enzyme which converts PGG.sub.2 and PGH.sub.2 to prostacycline (PGI.sub.2). The PGI.sub.2 has a function of inhibiting coagulation of blood platelets of a strength competine with the function of TXA.sub.2. In view of the above, it has been considered that the balance between the TXA.sub.2 and the PGI.sub.2 is important in connection with the formation of thrombus.
In the case of not only the thrombosed diseases but the blocked arteria diseases, it is known that the TXB.sub.2 (stabilizing product of metabolism of TXA.sub.2) value of the patient assumes a significantly high value as compared to that of a healthy person. This suggests that the blood platelets of such a patient are in a condition of easy coagulating, and in view of this tendency, a variety of blood platelet coagulation inhibitors are increasingly used for the prevention or remedy of these diseases in recent clinical treatments.
Furthermore, inhibition of metastasis of cancer by the use of an anti-Thrombus agent or drug has been tried recently.
Meanwhile, the blood platelet coagulation inhibitors presently used in clinical applications may be divided into following two groups in consideration of their functions or effects.
The first group includes those which are "inhibitors for synthesis of prostaglandin in blood platelets"; and the second groups includes those which are "inhibitors for c-AMP phosphodiesterase" or "accelerators for adenylate cyclase."
Known inhibitors for synthesis of prostaglandine in blood platelets, are Aspirin, indomethacine and imidazole derivatives.
As the "inhibitors for c-AMP phosphodiesterase" or "accelerators for adenylate cyclase", papaverine and dipyridamol have been known for the former and ticlopidine has already been known and used widely for the latter.
It has been further recognized recently that Aspirin, dipyridamol and ticlopidine have the effect of inhibiting metastasis of cancer as shown by the results of experiments using animals.
However, an excellent blood platelet coagulation inhibitor has not yet been found from the group of pyrimido[2,1-b]benzothiazole derivatives.
According to one of its aspects, this invention has as its object to provide a pyrimido[2,1-b]benzothiazole derivative which has improved function of inhibiting coagulation of blood platelets that is superior to various known blood coagulation inhibitors.